Utility of Post-Mortem Genetic Testing in Cases of Sudden Arrhythmic Death Syndrome

作者：Lahrouchi Najim; Raju Hariharan; Lodder Elisabeth M; Papatheodorou Efstathios; Ware James S; Papadakis Michael; Tadros Rafik; Cole Della; Skinner Jonathan R; Crawford Jackie; Love Donald R; Pua Chee J; Soh Bee Y; Bhalshankar Jaydutt D; Govind Risha; Tfelt Hansen Jacob; Winkel Bo G; van der Werf Christian; Wijeyeratne Yanushi D; Mellor Greg; Till Jan; Cohen Marta C; Tome Esteban Maria; Sharma Sanjay; Wilde Arthur A M; Cook Stuart A; Bezzina Connie R

来源：Journal of the American College of Cardiology, 2017, 69(17): 2134-2145.

DOI：10.1016/j.jacc.2017.02.046

• cardiomyopathy
• channelopathy
• molecular autopsy
• next-generation sequencing
• unexplained sudden death

BACKGROUND Sudden arrhythmic death syndrome (SADS) describes a sudden death with negative autopsy and toxicological analysis. Cardiac genetic disease is a likely etiology.
OBJECTIVES This study investigated the clinical utility and combined yield of post-mortem genetic testing (molecular autopsy) in cases of SADS and comprehensive clinical evaluation of surviving relatives.
METHODS We evaluated 302 expertly validated SADS cases with suitable DNA (median age: 24 years; 65% males) who underwent next-generation sequencing using an extended panel of 77 primary electrical disorder and cardiomyopathy genes. Pathogenic and likely pathogenic variants were classified using American College of Medical Genetics (ACMG) consensus guidelines. The yield of combined molecular autopsy and clinical evaluation in 82 surviving families was evaluated. A gene-level rare variant association analysis was conducted in SADS cases versus controls.
RESULTS A clinically actionable pathogenic or likely pathogenic variant was identified in 40 of 302 cases (13%). The main etiologies established were catecholaminergic polymorphic ventricular tachycardia and long QT syndrome (17 [6%] and 11 [4%], respectively). Gene-based rare variants association analysis showed enrichment of rare predicted deleterious variants in RYR2 (p = 5 x 10(-5)). Combining molecular autopsy with clinical evaluation in surviving families increased diagnostic yield from 26% to 39%.
CONCLUSIONS Molecular autopsy for electrical disorder and cardiomyopathy genes, using ACMG guidelines for variant classification, identified a modest but realistic yield in SADS. Our data highlighted the predominant role of catecholaminergic polymorphic ventricular tachycardia and long QT syndrome, especially the RYR2 gene, as well as the minimal yield from other genes. Furthermore, we showed the enhanced utility of combined clinical and genetic evaluation.

• 出版日期2017-5-2